Novel peripheral mechanisms of opioid analgesia

1997 ◽  
Vol 20 (3) ◽  
pp. 465-466
Author(s):  
Christoph Stein ◽  
Michael Schäfer
Keyword(s):  
Cell Proliferation ◽  
Side Effects ◽  
Opioid Peptides ◽  
Immune Cell ◽  
Opioid Analgesia ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid ◽  
Injury Site ◽  
Underlying Mechanisms ◽  
Peripheral Opioid Receptors

dickenson briefly mentions that peripheral opioid receptors somehow become active following inflammation and that the appearance of endogenous opioid peptides at the injury site may be related to immune cell proliferation. Recent findings elucidate the underlying mechanisms in more detail and provide an incentive for the development of a novel generation of analgesics devoid of typical central opioid side effects.

scholarly journals Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects

2021 ◽  
Vol 118 (16) ◽  
pp. e2000017118
Author(s):  
Ram Kandasamy ◽  
Todd M. Hillhouse ◽  
Kathryn E. Livingston ◽  
Kelsey E. Kochan ◽  
Claire Meurice ◽  
...  
Keyword(s):  
Side Effects ◽  
G Protein ◽  
Opioid Receptor ◽  
Opioid Peptides ◽  
Chinese Hamster ◽  
Mu Opioid Receptor ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid ◽  
Mu Opioid

Positive allosteric modulators (PAMs) of the mu-opioid receptor (MOR) have been hypothesized as potentially safer analgesics than traditional opioid drugs. This is based on the idea that PAMs will promote the action of endogenous opioid peptides while preserving their temporal and spatial release patterns and so have an improved therapeutic index. However, this hypothesis has never been tested. Here, we show that a mu-PAM, BMS-986122, enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in Chinese hamster ovary (CHO) cells expressing human mu-opioid receptors. Moreover, BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray, an important site for antinociception. We describe in vivo experiments demonstrating that the mu-PAM produces antinociception in mouse models of acute noxious heat pain as well as inflammatory pain. These effects are blocked by MOR antagonists and are consistent with the hypothesis that in vivo mu-PAMs enhance the activity of endogenous opioid peptides. Because BMS-986122 does not bind to the orthosteric site and has no inherent agonist action at endogenously expressed levels of MOR, it produces a reduced level of morphine-like side effects of constipation, reward as measured by conditioned place preference, and respiratory depression. These data provide a rationale for the further exploration of the action and safety of mu-PAMs as an innovative approach to pain management.

Do Endogenous Opioid Peptides Cause Hepatic Encephalopathy?

1987 ◽  
Vol 72 (s16) ◽  
pp. 90P-91P
Author(s):  
J.R. Thornton ◽  
M.S. Losowsky
Keyword(s):  
Hepatic Encephalopathy ◽  
Opioid Peptides ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid

Met5-enkephalin protects isolated adult rabbit cardiomyocytes via δ-opioid receptors

1999 ◽  
Vol 277 (6) ◽  
pp. H2442-H2450 ◽  
Author(s):  
Yasushi Takasaki ◽  
Roger A. Wolff ◽  
Grace L. Chien ◽  
Donna M. van Winkle
Keyword(s):  
Cell Death ◽  
Opioid Receptors ◽  
Ischemic Preconditioning ◽  
Opioid Peptides ◽  
Trypan Blue ◽  
Adult Rabbit ◽  
Endogenous Opioid Peptides ◽  
Endogenous Opioid ◽  
Simulated Ischemia ◽  
Hypoxic Incubation

In rats and rabbits, endogenous opioid peptides participate in ischemic preconditioning. However, it is not known which endogenous opioid(s) can trigger cardioprotection. We examined preconditioning-induced and opioid-induced limitation of cell death in isolated, calcium-tolerant, adult rabbit cardiomyocytes. Cells were subjected to simulated ischemia by pelleting and normothermic hypoxic incubation. Preconditioning was elicited with 15 min of simulated ischemia followed by 15 min of resuspension and reoxygenation. All cells underwent 180 min of simulated ischemia. Cell death was assessed by trypan blue permeability. Morphine protected cells, as did preconditioning; naloxone blocked the preconditioning-induced protection. Exogenous Met5-enkephalin (ME) induced protection, but exogenous β-endorphin did not. ME-induced protection was blocked by the δ-selective antagonist naltrindole. Additionally, two other proenkephalin products, Leu5-enkephalin and Met5-enkephalin-Arg-Phe, provided protection equipotent to ME. These data suggest that one or more proenkephalin products interact with δ-opioid receptors to endogenously trigger opioid-mediated protection.

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